The invention is directed to novel 9-hydroxyalkylamino- and 9-alkoxyalkylamino-1-nitroacridine derivatives. Methods of preparation, compositions comprising said derivatives and their medical uses are also encompassed by this invention.
Acridines are potent biological molecules that bind to DNA and inhibit cell growth. A number of derivatives of acridine have been studied for antitumor activity. Earlier work showed that 1-nitro-9-alkylaminoalkylaminoacridines had good antitumor activity (see, for example, U.S. Pat. No. 4,139,531, Gniazdowsk et al., 1995, Gen. Pharmacol. 26:473, Ledochowski, 1976, Mat. Med. Pol. 3:237, Mazerska et al., 1984, Eur. J. Med. Chem. 19:199, Pawlak et al., 1984, Cancer Res. 44:4289, Mazerska et al., 1990, Anti-Cancer Drug Des. 5:169, Hrabowska et al., 1982, Arzneim-Forsch./Drug. Res. 32:1013-1016). It has been found that introduction of a hydroxyalkyl amino group into position 9 of 1-nitroacridine, also provides active compounds (EP 38572).
Despite a large body of data on derivatives of acridines (Mazerska, Z. et al., 1984 Eur. J. Med. Chem. 19: 1999; Mazerska, Z. et al., 1990, Anticancer Drug Des. 5:169), the introduction of new substituents into the system still can provide unexpected results. As an illustration, studies on mutagenicity of various derivatives of nitracrine demonstrated different characteristics for individual compounds (Ferguson et al. 1987, Mutagenesis 2:253). It was also found that the introduction of 4-methoxy substituent into nitracrine moiety decreased the overall metabolism in comparison with the unsubstituted compound in rat (Robertson et al., 1996, Xenobiotica 26:559). A 3,4-dimethoxyacridine derivative having in position 9 a hydroxyethylamino substituent was found to be less potent than the corresponding dimethylaminoethylamino compound (Monge, A. et al., 1994, J. Heterocyclic Chem. 31:1455).
Acridine multi-substituted derivatives possessing nitro, methoxy, methyl, aminoalkylamino or hydroxyalkylamino substituents are known, and some have been studied as potential anticancer agents (Horowska et al., 1968, Rocz. Chem. 42:1351; Steck, E. A. et al., 1957, J. Am. Chem. Soc. 79:4414; Monge. et al., 1994, J. Heterocyclic Chem. 31:1455; Wilson et al., 1989, J. Med Chem. 32:23; Wysocka-Skrzela et al., 1981, Pol. J. Chem. 55:2211; Cholody, et al., 1983, Pol. J. Chem. 57:285; Cain et al., 1974, J. Med. Chem. 173:922; Cholody, et al., 1991, J. Heterocyclic Chem. 28: 209; U.S. Pat. No. 2,762,809; Yekundi, et al., 1957, Chem. Ber. 90:2448). However, the effectiveness of these compounds in inhibiting tumor growth varies.
There is a need for more nontoxic and effective antitumor agents. An objective of the present invention is to provide novel 9-alkylamino-1-nitroacridine derivatives as anticancer agents with an enhanced therapeutic index.
The invention is directed to novel 1-nitroacridine derviative(s), to methods for their preparation, as well as compositions comprising such derivatives. The invention is also directed to methods of using such derivatives and compositions to inhibit or prevent growth of tumors and/or prevent or inhibit metastases in a mammal, particularly a human patient by administering to such mammal an amount of said derivatives or compositions effective to inhibit or prevent growth of a tumor(s) and/or prevent or inhibit metastases in said mammal. The invention is further directed to the use of these derivatives for the manufacture of a medicament for prevention or inhibition of tumor growth and/or prevention of metastases. In a particular embodiment, the tumor is selected from the group consisting of prostate tumor, colon tumor, lymphoma, breast tumor, leukemia, and/or sarcoma. In a most particular embodiment, the tumor is a prostate tumor.
The invention is additionally directed to methods of using such derivatives and compositions to inhibit or prevent viral, parasite, bacteria (e.g., Staphylococcus, Streptococcus, Niseria), and/or fungal growth or infection comprising administering to a mammal, particularly a human patient an amount of said derivatives and compositions effective to inhibit or prevent microorganism, particularly, viral, bacterial, parasite and/or fungal growth or infection. The invention is further directed to the use of these derivatives for the manufacture of a medicament for prevention or inhibition of viral, bacterial, parasite and/or fungal growth or infection.
The derivative of the present invention has the structure, I 
wherein when R1 is H, R2 is H or CO(CH2)nCH3, where n=1-8, R3 is H, (CH2)nCH3, where n=0-1 or O(CH2)nCH3, where n=0-1 and R4 is H, (CH2)nCH3, or O(CH2)nCH3, where n=0-1;
wherein when R1 is O(CH2)nCH3, where n=0-1, and R2 is H, R3 and R4 is H and
wherein when R1 is O(CH2)nCH3, where n=0-1 and R2 is CO(CH2)nCH3, where n=1-8, R3 is H, (CH2)nCH3, where n=0-1 or O(CH2)nCH3, where n=0 xe2x88x921, and R4 is H, (CH2)nCH3, or O(CH2)nCH3, where n=0-1 or salts thereof.
Examples of salts include but are not limited to the acid-addition salts, particularly, the non-toxic, acid addition salts. Acids useful for preparing the acid-addition salts include, inter alia, inorganic acids, such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid and organic acids, such as lactic, methanesulfonic acid, oxalic, maleic, tartaric, citric, acetic and succinic acid.
In a specific embodiment, the 1-nitroacridine derivatives are selected from the group consisting of 9-(2xe2x80x2-hydroxyethylamino)-4-methyl-1-nitroacridine, 9-(2xe2x80x2-hydroxyethylamino)-7-methoxy-1-nitroacridine, 9-(2xe2x80x2-hydroxyethylamino)-7-methoxy-4-methyl-1-nitroacridine, 9-(2xe2x80x2-acetoxyethylamino)-1-nitroacridine, 9-(2xe2x80x2-propionoxyethylamino)-1-nitroacridine, 9-(3xe2x80x2-hydroxypropylamino)-7-methoxy-1-nitroacridine, 9-(3xe2x80x2-hydroxypropylamino)-4-methyl-1-nitroacridine, 9-(2xe2x80x2-acetoxyethylamino)-4-methyl-1-nitroacridine, 9-(2xe2x80x2-propionoxyethylamino)-4-methyl-1-nitroacridine, 9-(3xe2x80x2-acetoxypropylamino)-4-methyl-1-nitroacridine, 9-(2xe2x80x2-propionoxypropylamino)-4-methyl-1-nitroacridine, 9-(2xe2x80x2-hydroxyethylamino)-4-methoxy-1-nitroacridine, 9-(3xe2x80x2-hydroxypropylamino)-4-methoxy-1-nitroacridine, 9-(4xe2x80x2-hydroxybutylamino)-4-methoxy-1-nitroacridine, 9-(4xe2x80x2-hydroxybutylamino)-7-methoxy-1-nitroacridine and 9-(2xe2x80x2-acetoxyethylamino)-7-methoxy-4-methyl-1-nitroacridine, 9-(3xe2x80x2-hydroxypropylamino)-7-methoxy-4-methyl-1-nitroacridine, 9-(4xe2x80x2-hydroxypropyl amino)-7-methoxy-4-methyl-1-nitroacridine, 9-(3xe2x80x2-acetoxypropylamino)-7-methoxy-4-methyl-1-nitroacridine, 9-(2xe2x80x2-butyloxyethylamino)-4-methyl-1-nitroacridine,